Modulation of the toxicity and antitumour activity of alkylating drugs by steroids

Abstract

Summary.-The steroids prednisolone and progesterone significantly altered the therapeutic indices of the alkylating agents, nitrogen mustard, melphalan, cyclophosphamide, phenyl acetic mustard and chlorambucil. For nitrogen mustard, chlorambucil and phenyl acetic mustard, prednisolone reduced host toxicity in the rat and enhanced the antitumour effectiveness against alkylating-agent-resistant strains of the Yoshida sarcoma and Walker carcinosarcoma. Progesterone also increased the therapeutic index of chlorambucil in the rat by decreasing its systemic toxicity.Two other alkylating agents, melphalan and cyclophosphamide, exhibited lower therapeutic indices in combination with prednisolone against alkylating-agentsensitive tumours. This was due to the greater host toxicity of the combination than of the alkylating agent alone. In alkylating-agent-resistant tumours, however, a significant increase in growth delay was achieved if prednisolone was combined with the alkylating agent.

Temporal Factors Alter Effects of Social Housing Conditions on Responses to Chemotherapy and Hormone Levels in a Shionogi Mammary Tumor Model

“…In animals, like in humans, exposure to a stressful event typically causes physiological changes, including increased synthesis of corticosterone (CORT; cortisol in humans), decreased synthesis of gonadal and growth hormones, and suppression of the immune response (9,10). Relevant to the present study, altered hormone levels have been correlated with changes in tumor growth rates and differential responses to cancer treatments (11)(12)(13)(14). Thus, stressor-induced alterations in endocrine functioning may play a role in mediating the effects of stressful life events on cancer growth and treatment.…”

“…cacy are poorly understood, there is some evidence that alterations in circulating hormone levels (including CORT, GH, and/or T) (12,18,20) with or without immune system involvement (13,19,24,25,30) may influence the effectiveness of chemotherapy treatment. A major goal of the present study was to determine if the temporal relationships among tumor cell injection, formation of experimental housing conditions, and chemotherapy administration differentially affect CORT, T, and GH levels and whether changes in these hormones are related to the differential tumor and host responses to chemotherapy observed.…”

“…The timing of hormone administration relative to chemotherapy initiation also can differentially influence tumor response to chemotherapy. For example, T administered before but not after CY treatment increases the cytotoxic effects of CY (19), whereas the antitumor effects of CY are decreased by an increase in CORT levels before CY administration (12,20). However, an increase in CORT levels may also have beneficial effects in terms of host response to chemotherapy by protecting the animal from the toxic side effects of cytotoxic drugs (21,22).…”

Synergistic killing of human leukaemic lymphoblasts by glucocorticoids and cytosine arabinoside

“…Synergism would occur in protocol 2 if the presence of steroid could potentiate minor damage caused by Ara-C to a degree which results in cell death. Such a mechanism would be similar to the synergism between glucocorticoids and various alkylating agents which has been observed in cells which are not lysed by glu,cocorticoids (Harrap et al, 1977; Shepherd & Harrap, 1982;Tew et al, 1982). Since both Ara-C and the alkylating agents are known to damage DNA, it is possible that glucocorticoids interfere with DNA repair mechanisms and so diminish the ability of cells to recover from exposure to these drugs.…”

Structure of N-(2-chloroethyl)-2-furamide

“…For this reason they are called compounds with radiomimetic action (Dustin, 1947). Many of them are in use as drugs in chemotherapy of neoplastic diseases (Shephard & Harrp, 1982;Denny & Wilson, 1986). Among others, N-(2-chloroethyl)-2-furamide has been synthetized (Vlahov, 1976) and tested on lymphohematopoietic cells (Vlahov, 1982;Vlahov & Volf, 1983).…”